Perioperative myocardial infarction is a common and potentially fatal complication after noncardiac surgery, particular among patients with cardiovascular risk factors. β-blockers have been considered a mainstay in prevention and treatment of perioperative myocardial infarction, yet recent evidence suggests that β-blockers may have an unfavorable risk profile in this setting, and the use has become controversial. What seems conspicuously absent from the current discussion is the appreciation of how much interindividual genetic variation influences the clinical response to β-blocker therapy. Genetic variation in the adrenergic signaling pathway is common, and has a major impact on adrenergic receptor function and β-blocker efficacy in other cardiovascular diseases, such as heart failure and hypertension. Genetic variation in the cytochrome P450 2D6, or CYP2D6, enzyme, which is responsible for the metabolism of most β-blockers, is also important and can lead to poor metabolizing of β-blockers (potential toxicity) or their ultra-rapid degradation (decreased efficacy). Here, we review the molecular, cellular, and physiologic consequences of polymorphisms in the adrenergic signaling pathway and CYP2D6 gene, and show that these are likely relevant factors influencing efficacy, safety, and toxicity of β-blocker therapy in prevention and treatment of perioperative myocardial infarction.